European Patent Application No. 004913 as laid open describes inter alia a process for the production of 17-C-steroid-.alpha.-propionic acid compounds, particularly 3-oxo-pregna-4-ene-20-carboxylic acid (.DELTA.4-BNC) and/or 3-oxo-pregna-1,4-diene-20-carboxylic acid (.DELTA.1,4-BNC), by microbial side chain degradation on 17 C-side chain steroid substrates. By using microorganism defect mutants grown and selected in a certain manner, which give steroid compounds containing the 17 C-.alpha.-propionic acid residue even in the absence of inhibitors which inhibit degradation of the steroid ring and/or growth inhibitors, it is possible to obtain .DELTA.4-BNC and, in particular, .DELTA.1,4-BNC in commercial quantities. Another embodiment of this process is described in European Patent Application No. 0015308.
These .DELTA.1,4-BNC compounds formed by the side chain degradation of natural sterol compounds contain a functional group in only the 3-position of the ring system. However, all pharmacologically active corticosteroids contain additional oxygen functions and, in some cases, other functional groups in the molecule. The 9,11,17 and 21 positions are particularly important in this respect. Normally some of the oxygen functions are chemically introduced, including in particular the 17 and 21 positions.
By contrast, oxidation of the 11-position in steroid compounds is preferably carried out microbially. Several such microbial steroid oxidation processes are described in the specialist literature. In this connection, reference is made to the following publications and to the original Articles quoted therein: F. Drawert "Biosynthese von Hydroxy-Verbindungen (Biosynthesis of Hydroxy Compounds)"; Houben-Weyl "Methoden der organischen Chemie" (1978) 6/1d, pages 378 to 388; T. H. Stoudt, Adv. Appl. Microbiol. 2 (1960), pages 190 to 195; and W. Charney and H. L. Herzog "Microbial Transformations of Steroids" Academic Press (1967), New York, page 29.
Certain BNC-compounds containing an oxygen function in the 11-position and, in particular, 11-hydroxyl groups are described in German Offenlegungsschrift No. 28 39 033. This Offenlegungsschrift describes inter alia 11 .alpha.- and 11 .beta.-hydroxy-.DELTA.1,4-BNC and their production. It also describes the dehydration of these compounds to form the corresponding BNC compounds containing an additional double bond in the 9(11)-position. This dehydration process may be carried out in known manner, for example by converting the 11-hydroxyl compounds by reaction with methane sulfonic acid chloride or p-toluene sulfonic acid chloride into the corresponding sulfonic acid esters and converting the acid esters thus obtained into the corresponding .DELTA.9(11)-steroids by treatment with weak bases, such as sodium acetate. However, dehydration may also be carried out by heating the above-mentioned starting compounds with mineral acids, for example sulfuric acid, phosphoric acid or hydrochloric acid, in an inert solvent, such as benzene, toluene or xylene.
European Patent Application No. 11235, which is not a prior publication, describes 9-hydroxylated BNC-compounds and a process for their production. The description relates in particular to 9.alpha.-hydroxy-pregna-4,17(20)-diene-3-one-20-carboxylic acid.
9.alpha.-OH-.DELTA.4-BNC is described in U.S. Pat. No. 4,062,880 which also mentions the transformation of its methyl ester into the ester of .DELTA.4,9(11)-BNC by dehydration.